tbuckley/cabot-search huggingface dataset:
Abstract 2863: Interferon-gamma induces NOS2 and COX2 in ER- breast cancer that drives increase metastatic potential
Authors: Yuk Sing Robert Cheng, Lisa Ridnour, Abigail Walke, Noemi Kedei, Adelaide Wink, Elijah Edmonston, Donna Butcher, Tiffany Dorsey, William Heinz, Richard Bryant, Robert Kinders, Stanley Lipkowitz, Stephen Wong, Milind Pore, Stephen Hewitt, Daniel McVicar, Stephen Anderson, Jenny Chang, Stefan Ambs, Stephen Lockett, David Wink
Journal: Cancer Research (2023)

Abstract NOS2 and COX2 expression is significantly correlated with poor prognosis in ER- breast cancer. Multiple pro-oncogenic pathways involving metastasis, proliferation, angiogenesis, immunosuppression, and chemoresistance are stimulated in a synergistic manner by NOS2 and COX2, resulting in much more aggressive cancers. In this study, our single-cell RNAseq data demonstrated that certain combinations of cytokines, IFNg with TNFA or IL1B, drove NOS2 and COX2 expressions in vitro in the MDA-MB-231 cell line after 48 hours. Analysis of t-SNE plots indicates that the clustering patterns of NOS2 and COX2 are also related to cytokine expression. Moreover, according to our spatial proteomic analysis, CD8 that are associated with IFNg are more likely to have a positive response, indicating a dichotomy in the requirement for IFNg. To better understand this mystery, the spatial distribution of NOS2 and COX2 with CD8 cells in 21 ER- breast tumors was evaluated. In the presence of tumor-excluded CD8, high expression and clustering of NOS2-positive cells were seen near the tumor-stromal interface, showing that NOS2-positive cells were excluded from the tumor. Within the tumor nest, strong expression and population clustering of COX2 reached into the immune desert. In contrast, tumor-penetrant CD8 cells were few and poorly expressed. Metastasis and chemoresistance were among the leading causes of death in this cohort, and it was shown in vitro that IFNg/IL1B or TNFA increased tumor cell migration, suggesting that the interface of tumor with stromal restricted lymphoid aggregates provides the unique spatial environment to increase NOS2 expression and increase metastatic potential. The spatial study of the TME (tumor microenvironment) provides vital insight into how NOS2 and restricted CD8 lead to a higher probability of poor survival. Citation Format: Yuk Sing Robert Cheng, Lisa Ridnour, Abigail Walke, Noemi Kedei, Adelaide Wink, Elijah Edmonston, Donna Butcher, Tiffany Dorsey, William Heinz, Richard Bryant, Robert Kinders, Stanley Lipkowitz, Stephen Wong, Milind Pore, Stephen Hewitt, Daniel McVicar, Stephen Anderson, Jenny Chang, Stefan Ambs, Stephen Lockett, David Wink. Interferon-gamma induces NOS2 and COX2 in ER- breast cancer that drives increase metastatic potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2863.
Abstract 1332: Extracted mRNA from frozen buffy coat samples shows promise for use in downstream sequencing analyses
Authors: Erik Bovinder Ylitalo, Linda Vidman, Sophia Harlid, Bethany Van Guelpen
Journal: Cancer Research (2023)

Abstract Frozen blood samples are routinely collected and stored in medical biobanks across the world, often for periods of several decades, and later used for medical research such as biomarker studies. Some common biomarker targets have included DNA alterations, protein or antibody levels or metabolomics. However, despite the potential importance of gene-expression alterations in circulating immune cells, transcriptional studies on blood samples from biobanks have been limited due to preanalytical technical difficulties of extracting high-quality RNA. In the absence of an RNA preservative, RNA degrades rapidly during the thawing process. Our aim was, therefore, to investigate the possibility of using biobanked blood samples for transcriptomics analyses. First, we used a CryoXtract CXT 350 to establish a protocol capable of isolating high-quality RNA from frozen core aliquots of buffy coat without thawing the entire sample tube. Then, we performed RNA sequencing on RNA extracted from 20 pre-diagnostic buffy coat samples from colorectal cancer patients and matched controls included in the population-based, prospective Northern Sweden Health and Disease Study (NSHDS). For all samples, two different library preparation methods were used (Illumina TruSeq Stranded mRNA poly-A selection and Illumina Stranded Total RNA with Ribo-Zero Globin). We obtained RNA yields of more than 1 µg from a majority of the NSHDS samples (mean=2.57 µg), and more than 92% of samples had RIN values of 6 or higher, indicating suitability for downstream analyses. Preliminary random forest analyses showed expected discriminatory ability between men and women based on data generated from each of the two library preparation methods. In conclusion, our newly established RNA extraction method enables extraction of RNA from frozen, biobanked buffy coat samples, collected in standard tubes, that is of sufficient quantity and quality for use in downstream whole-genome transcriptomic analyses, such as RNA sequencing. Citation Format: Erik Bovinder Ylitalo, Linda Vidman, Sophia Harlid, Bethany Van Guelpen. Extracted mRNA from frozen buffy coat samples shows promise for use in downstream sequencing analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1332.
Abstract 1439: <i>In vivo</i> characterization of a selective FGFR2 inhibitor with potency against gatekeeper and molecular brake mutations
Authors: John Fischer, Karyn Bouhana, Mark Chicarelli, Brad Fell, Jennifer Fulton, Anna Guarnieri, Leyla Haygood, Ravi Jalluri, Amber Johnson, Brent Mclean, Max Mejia, Rob Rieger, John Robinson, Mareli Rodriguez, Francis Sullivan, Yang Wang, Shannon Winski, YeYun Zhou
Journal: Cancer Research (2023)

Abstract Fibroblast growth factor receptor (FGFR) mutations, fusions, and rearrangements have been linked to the pathogenesis of multiple tumor types. FGFR2 alterations have emerged as oncogenic drivers across a variety of tumor types, including cholangiocarcinoma, lung, endometrial, and uterine cancer. Approved FGFR inhibitors have demonstrated responses in patients that harbor FGFR genetic alterations but show reduced activity in patients with gatekeeper and molecular brake mutations. In addition, pan-FGFR inhibitors are associated with dose-limiting hyperphosphatemia linked to the inhibition of FGFR1. To address these issues, a novel series of reversible FGFR2 inhibitors with activity against clinically relevant mutations and selectivity over FGFR1 has been identified. The inhibition of FGFR2 phosphorylation in engineered cell lines demonstrated activity toward wild-type FGFR2, molecular brake mutations N549H/K, and gatekeeper mutations V564I/F/L. Selectivity of these inhibitors against FGFR1 and the broader kinome could lead to fewer dose limiting toxicities compared to approved FGFR inhibitors. Additionally, maintaining potency against molecular brake and gatekeeper mutations may result in significantly improved clinical response. In vivo characterization to be presented includes dose escalating rodent pharmacokinetics (PK), second species PK, and pharmacodynamics (PD) in tumor bearing mice. Most importantly, efficacy in a mouse tumor xenograft model at a dose that does not show elevated plasma phosphorus levels in the rat hyperphosphatemia model will be presented. Herein, the in vitro and in vivo characterization of a representative selective reversible FGFR2 inhibitor is described. Citation Format: John Fischer, Karyn Bouhana, Mark Chicarelli, Brad Fell, Jennifer Fulton, Anna Guarnieri, Leyla Haygood, Ravi Jalluri, Amber Johnson, Brent Mclean, Max Mejia, Rob Rieger, John Robinson, Mareli Rodriguez, Francis Sullivan, Yang Wang, Shannon Winski, YeYun Zhou. In vivo characterization of a selective FGFR2 inhibitor with potency against gatekeeper and molecular brake mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1439.
Abstract 3347: Characterization of extracellular POTE-2 protein in liver cancer
Authors: Samantha Lopez, Kyle D. Doxtater, Adithya Anilkumar, Sophia Leslie, Amayrani Sanchez, Kristopher Ezell, Subhash Chauhan, Manish K. Tripathi
Journal: Cancer Research (2023)

Abstract Liver cancer is projected to be the 5th and 7th leading cause of mortality in males and females in 2022. The top two forms of liver cancer diagnosed are hepatocellular carcinoma and cholangiocarcinoma, with a percentage of 75% and 11%. In recent years, Texas has had the highest incidence, with a rate of 11.6 per 100,000, with the Hispanic population having one of the highest rates. In South Texas, the Rio Grande Valley contains a high Hispanic population and faces multiple health disparities leading to a higher prevalence of liver cancer. These factors and the insufficient diagnostic methods for liver cancer lead to a need to identify faster and early biomarkers. Recently, we have identified an extracellular cancer-testis antigen, POTE-2, which belongs to the POTE gene family. Our preliminary data show that POTE-2 has an increased expression in liver cancer and can be associated with cancer progression. In this study, we will discuss the characterization of the extracellular face of POTE-2 in liver cancer. Lentiviral plasmids created an overexpressing and a knockdown POTE-2 cell line. The exosomes and conditioned media were collected from the cell lines to analyze POTE-2 protein expression through immunoblotting and ELISA. Antibodies targeting varying protein regions were produced and characterized for use in extracellular characterization. Exosome isolation and collection of conditioned media showed the expression of extracellular POTE-2 protein. Using varying antibodies targeting different regions determined the protein domain cleaved through secretion. These studies will aid in discovering novel characteristics of POTE-2 protein function and further explore its potential in liver cancer progression. Citation Format: Samantha Lopez, Kyle D. Doxtater, Adithya Anilkumar, Sophia Leslie, Amayrani Sanchez, Kristopher Ezell, Subhash Chauhan, Manish K. Tripathi. Characterization of extracellular POTE-2 protein in liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3347.
Abstract 6304: Preclinical development of a next generation antibody drug conjugate (ADC) targeting B7-H3 for treatment of solid tumors
Authors: Jian Xu, Qing Zong, Wei Wang, Qigang Liu, Sasha Stann, Jiaqiang Cai
Journal: Cancer Research (2023)

Abstract B7-H3 (CD276), an immune checkpoint member of the B7/CD28 family, is widely expressed in multiple cancers and is associated with poor prognosis. YL201 is a novel B7-H3-targeting antibody-drug conjugate (ADC) and built on MediLink’s tumor microenvironment activable linker-payload platform (TMALIN platform). This ADC is comprised of an anti-B7-H3 human monoclonal antibody conjugated to a novel topoisomerase 1 inhibitor via a protease-cleavable linker. The novel linker-payload and site-specific conjugation of YL201 results in a homogeneous and more hydrophilic ADC. In addition, the binding specificity, affinity and avidity of antibodies show no impact after conjugation. In vitro, upon binding to B7-H3, the antigen-ADC complexes are internalized to lysosomal vesicles releasing the toxic payload, whose cytotoxic features drive cell cycle arrest, apoptosis, elevation of PARP/caspase 7 expression, as well as cell death and bystander effect. In preclinical studies, YL201 is effective in causing tumor regressions in both cell line- and patient-derived xenograft (CDX and PDX) mouse models at doses that are well tolerated. The in vivo pharmacokinetics in monkeys showed that YL201 is deemed as ‘highly stable’ in circulation. Safety evaluations demonstrated acceptable safety profile and no off-target toxicity in monkeys. These non-clinical data suggest the stability of linker in circulation but efficiently release the payload in tumors, and eventually, expanded the therapeutic window. Taken together, preclinical data suggest that YL201 could be a promising treatment strategy for B7-H3 positive cancer patients. Citation Format: Jian Xu, Qing Zong, Wei Wang, Qigang Liu, Sasha Stann, Jiaqiang Cai. Preclinical development of a next generation antibody drug conjugate (ADC) targeting B7-H3 for treatment of solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6304.
Abstract 2923: JAB-X1800: A potent immunostimulatory antibody-drug conjugate (iADC) targeting CD73
Authors: Yang Ye, Guiqun Yang, Hongling Wang, Xin Sun, Yanping Wang, Fashun Yan, Lei Wang, Wei Long
Journal: Cancer Research (2023)

Abstract Background: STING emerges as a key immune sensor and activated STING pathway plays a key role in innate and adaptive immune response. STING agonist has shown promising potency to stimulate anti-tumor immunity. Considering immune-related toxicity due to systemic administration, as well as difficulty in intra-tumor administration, targeted delivery of STING agonist by iADC is warranted. We developed CD73-STING iADC JAB-X1800, which uses anti-CD73 mAb for targeted delivery of payload JAB-27670, a highly potent non-cyclic dinucleotide STING agonist. Method: Binding assay and HEK293-STING-luciferase reporter assay were performed to test affinity of JAB-27670. Tumor cells with CD73 expression and THP-1 cells were co-cultured in the presences of iADC JAB-X1800 to assess the IFN-β production. The cell killing activity of iADC JAB-X1800 was evaluated when cancer cells co-cultured with human PBMCs. Furthermore, human and mouse plasma stability of iADC JAB-X1800 was assessed. Finally, the anti-tumor effects of iADC JAB-X1800 alone or in combination with anti-PD-1 were evaluated in animal models. Results: JAB-27670 is a highly potent STING agonist with sub-nanomolar EC50 in binding and luciferase reporter assays. In CD73-expressing cancer cells and THP-1 co-culture experiments, iADC JAB-X1800 induced IFN-β production with significant improvement compared with the free payload. JAB-X1800 also induced potent killing in vitro. JAB-X1800 is stable in human and mouse plasma. A single dose of JAB-X1800 induced tumor regression in MDA-MB-231 xenograft model and hCD73-MC38 syngeneic model. JAB-X1800 conferred immunologic memory when tumor free mice were re-challenged. JAB-X1800 showed synergistic anti-tumor activity with anti-PD-1 in hCD73-MC38 syngeneic model. Conclusions: The CD73-targeted STING agonist iADC JAB-X1800 demonstrated high stability in plasma, robust activity, and good tolerability in animal models, supporting clinical development of JAB-X1800 alone and in combination with anti-PD-1 for patients with CD73-expressing tumors. Citation Format: Yang Ye, Guiqun Yang, Hongling Wang, Xin Sun, Yanping Wang, Fashun Yan, Lei Wang, Wei Long. JAB-X1800: A potent immunostimulatory antibody-drug conjugate (iADC) targeting CD73 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2923.
Abstract 1433: Targeting the mitotic kinase NEK2 potentiates CDK4/6 inhibitor efficacy in breast cancer
Authors: Jessica R. Bobbitt, Leslie Cuellar-Vite, Benjamin Bryson, Kristen Weber-Bonk, Ruth Keri
Journal: Cancer Research (2023)

Abstract Mitotic kinases are essential for cell cycle progression, and several mitotic kinase inhibitors have been developed to target the uncontrolled proliferation of cancer cells. However, despite their efficacy in preclinical models, mitotic kinase inhibitors are generally considered poor therapeutic targets due to their off target effects in other rapidly proliferating tissues and subsequent toxicity. However, preliminary data in our lab shows that relative to non-transformed cells, triple negative breast cancer (TNBC) cells are selectively sensitive to inhibition of the mitotic kinase NEK2 compared to other mitotic kinase inhibitors. Therefore, we hypothesize that NEK2 is a targetable vulnerability of TNBC. To begin to understand the role of NEK2 in TNBC, we performed RNA-sequencing following NEK2 silencing and found increased expression of genes important at the G1/S cell cycle transition. This transition is largely controlled by the RB-E2F signaling axis, where CDK4 and CDK6 are key players. CDK4/6 inhibitors have been FDA approved for the treatment of a subset of breast cancers. We investigated the impact of silencing NEK2 and treating with CDK4/6 inhibitors and found that loss of NEK2 sensitizes TNBC cells to CDK4/6 inhibition. Mechanistically, this combination causes a significant increase in genomic instability phenotypes. We tested the combination of NEK2 inhibition and CDK4/6 inhibition in vivo, and found that the combination significantly decreases mouse tumor volume without inducing toxicity. Mechanistically, the combination altered mitotic spindle genes in vivo, indicating an increase in genomic instability. Together, these data suggest that that NEK2 is a viable therapeutic target that could be used in combination with FDA approved CDK4/6 inhibitors for the treatment of aggressive breast cancers such as TNBC. Citation Format: Jessica R. Bobbitt, Leslie Cuellar-Vite, Benjamin Bryson, Kristen Weber-Bonk, Ruth Keri. Targeting the mitotic kinase NEK2 potentiates CDK4/6 inhibitor efficacy in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1433.
Abstract 2858: Radiotherapy and NK cell-based immunotherapy: An evolutionary double-bind
Authors: Kimberly Luddy, Jeffery West, Mark Robertson-Tessi, Bina Desai, Taylor M. Bursell, Sarah Barrett, Joel Brown, Jacintha O'Sullivan, Robert Gatenby, Laure Marignol, Alexander R. Anderson, Cliona O'Farrelly
Journal: Cancer Research (2023)

Abstract Evolution-informed therapies exploit the ecological and evolutionary consequences of drug resistance to inhibit the expansion of treatment resistant populations and prolong time to progression. One strategy, termed an evolutionary double-bind, uses an initial therapy to elicit a specific adaptive mechanism that is then selectively targeted by a follow-on therapy. Here we examine combining radiation therapy followed by immunotherapy as a double bind strategy. Radiotherapy (RT) induces lethal double-strand DNA breaks in tumor cells and radiosensitivity is governed by the cells’ DNA repair capabilities. Radioresistant cancer cells upregulate DNA damage response pathways. However, successful adaptations to RT and other DNA damaging agents can increase natural killer (NK) cell ligand expression on tumor cells increasing their vulnerability to the immune system. We conducted a multidisciplinary investigation of this potential evolutionary double bind using an isogenic cell line model of radiation resistance derived from an androgen-independent human prostate carcinoma cell line (22Rv1). We demonstrate that RT-resistant cells maintain higher expression of NK cell ligands and have a 2-fold increase in sensitivity to NK cell mediated killing. Furthermore, we show that preferential targeting of the RT-resistant population by NK cells is preserved in competition assays with varying initial population frequencies. Scope of treatment responses are dependent on population frequencies in our in vitro analysis. Mathematical modeling quantified three key elements of a double-bind: cost of resistance, inter-specific competition between RT-sensitive and RT-resistant lines, and preferential targeting of RT-resistant lines by NK cells. We conclude that RT followed by immunotherapy produces an evolutionary double bind that can be exploited in heterogenous tumors to limit RT resistance. Furthermore, model simulations predict that extinction of both populations is achievable by sequential RT and NK cell therapy. Citation Format: Kimberly Luddy, Jeffery West, Mark Robertson-Tessi, Bina Desai, Taylor M. Bursell, Sarah Barrett, Joel Brown, Jacintha O'Sullivan, Robert Gatenby, Laure Marignol, Alexander R. Anderson, Cliona O'Farrelly. Radiotherapy and NK cell-based immunotherapy: An evolutionary double-bind [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2858.
Abstract 2653: ABN501, a novel anti-claudin-3 antibody, shows potent anti-cancer activity <i>in vitro</i> and <i>in vivo</i>
Authors: Saehyung Lee, Jae Choi, Sunghyun Hong, Euni Sim, Jaemun Kim, Sangin Lee, Sungyoul Hong, Hobin Yang, Jiwon Jo, Na Young Kim, Young Kee Shin, Jun Young Choi
Journal: Cancer Research (2023)

Abstract Claudin-3, one of the tight junction proteins, could be a potential therapeutic target and biomarker. Since it is not only overexpressed in various types of malignant solid cancers but also exposed externally during tumorigenesis. Previously, we developed a fully human monoclonal antibody (ABN501) with sub-nanomolar affinity against the native claudin-3 protein. In this study, we confirmed that ABN501 is highly specific for the extracellular loop (ECL) 2 domain of claudin-3 using stable cell lines expressing two chimeric claudins fused to claudin-3 and claudin-4. Followed by, we evaluated in vitro ADCC activity of ABN501 using NK cells expressing CD16a (NK-92MI-CD16a), in various cancer cell lines, expressing claudin-3. ABN501 exhibited potent in vitro ADCC activity in diverse cancer cell lines. We also confirmed in vivo anti-tumor activity of ABN501 in xenograft mice bearing claudin-3-expressing tumors. In summary, we suggest that ABN501 can be used as promising tissue-agnostic drug candidates as therapeutics for various types of claudin-3-positive cancers. ABN501 is currently developed with various antibody engineering platforms. Citation Format: Saehyung Lee, Jae Choi, Sunghyun Hong, Euni Sim, Jaemun Kim, Sangin Lee, Sungyoul Hong, Hobin Yang, Jiwon Jo, Na Young Kim, Young Kee Shin, Jun Young Choi. ABN501, a novel anti-claudin-3 antibody, shows potent anti-cancer activity in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2653.